Apoptosis Signal-regulating Kinase 1 Silencing on Astroglial Inflammasomes in an Experimental Model of Ischemic Stroke

Neuroscience. 2018 Oct 15:390:218-230. doi: 10.1016/j.neuroscience.2018.08.020. Epub 2018 Aug 31.

Abstract

Activation of the inflammasome complex contributes to the inflammatory response and cell death under pathologic conditions. The nucleotide-binding oligomerization domain-like receptor pyrin domain-containing 2 (NLRP2) inflammasome is activated in astrocytes after cerebral ischemia, which can aggravate ischemic damage. Apoptosis signal-regulating kinase 1 (ASK1) is an early activator and immune-regulator after ischemic injury, that can lead to cell death. The objective of the present study was to evaluate the role of ASK1 in controlling NLRP2 inflammasomes in astrocytes after cerebral ischemia. In a mouse model of ischemic stroke, the levels of NLRP2 inflammasome components, and interleukin (IL)-1β and IL-18, were quantified in different brain regions. In addition, an astrocyte cell line was subjected to oxygen-glucose deprivation and reperfusion (OGD/R) injury, and the levels of NLRP2 inflammasome factors, IL-1β and IL-18 were evaluated. Ischemic brain injury activated astrocytes. The levels of NLRP2 inflammasome components, IL-1β and IL-18 productions, and cell death increased in the cortex and striatum after ischemic injury. In cultured astrocytes, NLRP2 inflammasome components, IL-1β and IL-18 levels were upregulated after OGD/R. ASK1 silencing or inhibition efficiently reduced NLRP2 inflammasome components and pro-inflammatory cytokine levels in mice and cultured astrocytes. Our findings identify a key role for ASK1 in regulating astroglial inflammasomes after cerebral ischemia. We suggest ASK1 as one of the main targets for astroglial inflammasomes in ischemic stroke.

Keywords: apoptosis signal-regulating kinase 1; astrocyte; inflammasomes; inflammatory response; ischemic stroke.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Adaptor Proteins, Signal Transducing
  • Animals
  • Apoptosis Regulatory Proteins
  • Astrocytes / metabolism*
  • Brain Ischemia / metabolism*
  • Cell Line
  • Disease Models, Animal
  • Inflammasomes / metabolism*
  • Inflammation / metabolism
  • MAP Kinase Kinase Kinase 5 / metabolism*
  • Male
  • Mice, Inbred C57BL
  • Proteins / metabolism*
  • Stroke / metabolism*

Substances

  • Adaptor Proteins, Signal Transducing
  • Apoptosis Regulatory Proteins
  • Inflammasomes
  • Nlrp2 protein, mouse
  • Proteins
  • MAP Kinase Kinase Kinase 5